rs121909224

Variant names:

• chr10-87933147-C-A
• rs121909224
• NM_000314.8:c.388C>A
• PTEN p.Arg130Arg

Your query was ambiguous. Multiple possible variants found:

• chr10-87933147-C-A
• chr10-87933147-C-G
• chr10-87933147-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). PM2BP4BP6_StrongBP7

The NM_000314.8(PTEN):c.388C>A (p.Arg130Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). The variant position is a cancer hotspot (cancerhotspots.org): 239 samples carry this exact amino acid change out of 1912 samples with a variant at this residue.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.57
• Publications: 0 publications found

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

PTEN Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Lhermitte-Duclos disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PTEN are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000104 by highest known P/LP ClinVar AF 0.000104) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.388C>A	p.Arg130Arg	synonymous	Exon 5 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.907C>A	p.Arg303Arg	synonymous	Exon 6 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.-363C>A		5_prime_UTR	Exon 4 of 9	NP_001291647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.388C>A	p.Arg130Arg	synonymous	Exon 5 of 9	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.907C>A	p.Arg303Arg	synonymous	Exon 6 of 10	ENSP00000509861.1	P60484-2
	PTEN	ENST00000700029.2		c.388C>A	p.Arg130Arg	synonymous	Exon 5 of 10	ENSP00000514759.2	A0A8V8TPK6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome Warning	AF: 0.00000137	AC:2	Hom:0	AN:1461670	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cowden syndrome 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
BayesDel_noAF	Benign	-0.16
CADD	Benign	14
DANN	Benign	0.73
GPN-Star LLR	N/A	-6.5
GPN-Star score	N/A	6.5
PhyloP100	Uncertain	5.6

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121909224;

hg19: chr10-89692904;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar